Research articles

Kyle Walsh and colleagues identify a variant near TERC associated with glioma susceptibility. They further show that glioma risk alleles near TERC and TERT are associated with longer mean telomere length in leukocytes, implicating telomerase activity in gliomagenesis.

David Kingsley and colleagues functionally investigate a previously identified GWAS region in an enhancer of the KITLG gene (encoding KIT ligand) that is significantly associated with blond hair color in northern European populations. They show that a single regulatory SNP, located 350,000 bp upstream of the human gene, reduces the activity of a tissue-specific hair follicle enhancer and is sufficient to alter hair color in mice.

Hai Yan, Zachary Reitman and colleagues report exome sequencing of resected tumor tissue from brainstem gliomas and thalamic gliomas and identify mutations in PPM1D in brainstem gliomas.

Richard Houlston, Maria Teresa Landi and colleagues report the identification of large-effect associations for squamous lung cancer with rare variants in BRCA2 and CHEK2.

François Spitz and colleagues identify cis-acting enhancers of Myc in a region orthologous to human 8q24 that are required for normal development of the face in mice. Their results shed light on the role of this region in facial deformities in humans, including cleft lip and palate.

Stephen Scherer and colleagues report an inverse relationship between exon transcription levels in the developing brain and the burden of rare missense mutations. Using these data, they develop a contingency index that identifies critical exons harboring deleterious de novo mutations that are enriched in individuals with ASD relative to their unaffected siblings.

Robert West, Jonathan Pollack and colleagues identify mutations in either the Hedgehog pathway gene SMO or the MAPK gene BRAF in 24 of the 28 ameloblastoma samples studied. They found 9 of 11 SMO mutations were found in maxillary ameloblastomas, whereas 9 of 13 BRAF mutations were found in mandibular cases.

Shumpei Ishikawa and colleagues report the identification of recurrent gain-of-function mutations in RHOA in diffuse-type gastric carcinomas.

Marc Ladanyi and colleagues identify a recurrent somatic mutation in MYOD1 in a subset of rhabdomyosarcomas with poor outcome. The mutation alters the DNA binding and transactivation properties of MYOD1 and promotes a switch from differentiation to proliferation.

Timothy Chan and colleagues show that the PARK2 tumor suppressor is a master regulator of G1 and S phase cyclins and is critical for proper cell cycle regulation. PARK2 genetic alterations are common across many human cancers as well as in hereditary Parkinson's disease.

Jonathan Fletcher and colleagues describe highly recurrent deletions of the large muscular dystrophy–associated gene DMD in gastrointestinal stromal tumors, rhabdomyosarcomas and leiomyosarcomas, all cancers with muscle differentiation. Re-expression of DMD in these tumor cells inhibits aspects of their metastatic phenotypes.

Xiangdong Fu and colleagues show that variation in DEP1, which encodes a G protein subunit known to influence rice panicle architecture, underlies a major quantitative trait locus for nitrogen-use efficiency. These findings suggest that modulating heterotrimeric G protein activity could contribute to environmentally sustainable increases in rice grain yield.

Guillaume Lettre, Alexander Reiner, George Diaz and colleagues use an exome array to identify rare and low-frequency coding variants influencing hematological traits. They find several missense variants in CXCR2 associated with reduced white blood cell counts, and, in a separate family-based study, they identify a homozygous CXCR2 frameshift mutation in two siblings with congenital neutropenia.

Lars Forsberg, Jan Dumanski and colleagues report that age-related loss of chromosome Y in peripheral blood is associated with increased risks of all-cause mortality, cancer mortality and non-hematological cancer mortality.

Bruce Gelb and colleagues identify rare RAF1 mutations in individuals with childhood-onset dilated cardiomyopathy in three cohorts from South India, North India and Japan. Variant RAF1 proteins show altered kinase activity that causes AKT hyperactivation.

Christel Depienne, Eric LeGuern and colleagues report the identification of 5 de novo missense mutations in HCN1 in individuals with early-onset epileptic encephalopathy. Functional studies confirmed the pathogenic nature of these mutations.

Richard Lifton and colleagues identify a recurrent activating mutation in PRKACA, which encodes the catalytic subunit of protein kinase A, in cortisol-producing adrenal tumors. They further show that the mutation results in loss of binding by the regulatory subunit PRKAR1A, leading to increased phosphorylation of downstream targets.

David Weinstock and colleagues identify a triplication at chromosome 21q22 that is associated with development of B cell acute lymphoblastic leukemia (B-ALL) that causes B cell self renewal in vitro. They further demonstrate that this triplication leads to overexpression of the nucleosome remodeling protein HMGN1 and loss of H3K27me3, implicating these changes in B-ALL.

Jérôme Bertherat, Aurélien de Reyniès and colleagues perform integrated genomic analyses of adrenocortical carcinomas. They discover recurrent alterations in several new driver genes, including ZNRF3, DAXX, TERT and MED12, and identify two distinct molecular subgroups with opposite clinical outcomes.

Heymut Omran and colleagues show that biallelic mutations in CCNO cause a chronic destructive lung disease resulting from loss of multiple motile cilia from the surface of respiratory epithelial cells. Subcellular analyses suggest that CCNO deficiency leads to defective centriole amplification and migration, leading to reduced ciliogenesis.